Projects

Aortic valve disease is one of the most common congenital heart defects and affects over 5% of children with heart disease. Often times, pediatric patients are treated by replacing or less commonly repairing the valve. The issue with clinically available valve implants for children is that they come at a fixed size and are incapable of growth. Thus, this requires multiple surgeries for valve revisions. Our goal is to address this need with a tissue engineered heart valve that is capable of growth and remodeling within a growing child. To do so, we are using induced pluripotent stem cells to generate patient specific valve cells. In addition, we are engineering cell-laden biomaterials to be 3D printed using 3D models generated from patient CT. Using this approach, we will generate a 3D tissue engineered heart valve that has the potential to grow and repair in a child.

Exosomes for Myocardial Repair

Exosomes are vesicles derived from cell membranes which are released either by the fusion of microvescicles with the cell membrane or directly by cell membrane. They carry various signals including micro-RNAs which can serve either as biomarkers or therapeutic agents in treating cardiovascular diseases including myocardial infarction (MI). In this project, we are looking at the effect of exosome delivery on heart function and regeneration in an ischemia reperfusion model of MI.

Bioactive Nanoparticles for Small Molecule Delivery to Cardiac Myocytes

Delivery of small molecules to the heart is limited by the ability of cardiomyocytes (CMs) to internalize substances. We have developed a drug delivery system for enhanced CM uptake by decorating degradable, biocompatible, polyketal nanoparticles with N-acetylglucosamine (GlcNAc) and demonstrated their ability to be internalized by cardiac myocytes. In addition to facilitating the delivery of functional small molecules and proteins to CMs, the GlcNAc molecule released from intracellular nanoparticle degradation can be used as a substrate for post-translational modification of calcium handling proteins in myocytes, hence making it a “bioactive” nanoparticle. Thus, the development of our bioactive nanoparticle allows for a “two-hit” treatment, by which the cargo and also the nanoparticle itself can modulate intracellular protein activity.

Specialized cells found in the heart, called cardiac progenitor cells (CPCs), have the ability to repair the injured heart and our lab has developed a method to isolate these cells from human tissue biopsies. While therapies using these cells have been demonstrated in clinical trials to be safe and feasible, their success has been limited by low cellular differentiation and cell retention. We propose the delivery of CPCs aggregated into scaffold-less 3D spheroids. The 3D microenvironment may recapitulate cell signaling interactions found in the cardiac stem cell niche to improve retention and differentiation of CPCs into mature cardiac phenotypes.

In collaboration with the Xia Lab, we are currently investigating the use of a biomimetic cardiac patch to enhance the reparative capabilities of pediatric human cardiac progenitor cells. We hope to utilize these patches to repair injured hearts and to provide treatment for patients with congenital heart defects.

Congenital heart defects effect 35,000 newborns annually, resulting in significant hindrance to heart function. Although surgical treatments have shown improvements, many children develop cardiac dysfunction and right ventricular failure. The main standard of care in these cases is transplantation, which is limited by donor availability and transplant rejection. In collaboration with the Christman lab at the University of California, San Diego, we are developing a heart patch, composed of cardiac matrix material and pediatric stem cells, for treatment of pediatric heart failure. The use of cardiac stem cells will allow for targeted and effective regeneration of heart function, while the inclusion of cardiac matrix will decrease hypertrophy and improve ejection fraction. The patch will be bioprinted for control of device structure and properties, allowing for a personalized treatment platform.

Optimizing PEG-based Bioinks to 3D Print Aortic Valves

Despite advances in 3D printing, there is a lack of suitable bioinks for 3D bioprinting. We seek to develop a PEG-based bioink suitable for printing aortic valves. We aim to optimize biocompatible hydrogels for 3D printing, characterize the mechanical properties of 3D printed constructs, and use the bioink to 3D print patient-specific aortic valves designed from the CT scans of healthy pediatric patients.

This project involves the screening and validation of miRNAs using an SAMcell assay. Validated miRNA targets will then be conjugated onto polyketal nanoparticles and delivered to a model of myocardial infraction. Heart function and repair will be evaluated following treatment.

Investigating the Role of Notch1 Activation In Cardiac Progenitor Cells

Cardiac progenitor cells (CPCs) are a population of cardiac stem cells that can differentiate to form cardiomyocytes, smooth muscle, or endothelial cells. Because of their regenerative capacity, CPCs are a prime candidate for cell-based therapies to repair the damage caused by myocardial infarction (MI). We are working to improve cell retention and differentiation by designing novel injectable biomaterials for CPC delivery. We are also interested in the importance of the Notch1 signaling pathway in promoting survival and differentiation of CPCs

Using Systems Biology and Bioinformatics to Identify Potenital Therapeutic RNA Clusters in hCPCs

The regenerative potential of cardiac progenitor cells (hCPCs) have been demonstrated in multiple studies indicating the repair of the myocardium following injury. In this project, we will sequence the RNA from a large pool of hCPCs that our lab has accumulated for miRNAs of interest. A bioinformatics/systems biology approach will be used to identify covariant miRNA clusters with respect to several parameters and identify any potential targets of interest for further study. Ideally, we hope to gain insight into the molecular mechanisms by which hCPCs regenerate cardiac tissue.

Identification of Targeting Peptides for the Detection of Myocarditis

Myocarditis is an inflammatory heart muscle disease associated with cardiac dysfunction. No current treatments or biological markers for myocarditis have been identified. The goal of this project is to use phage display to identify markers of myocarditis in an experimental autoimmune myocarditis (EAM) model in mice. Identified peptides will be tested for binding and determined if they can be used to diagnose myocarditis in vivo.

In collaboration with the Garcia lab, we are investigating the application of integrin-specific ligand presenting poly(ethylene glycol)-based hydrogels in conjunction with human cardiac progenitor cells for treating injured hearts.